Process for the Preparation of Sevelamer Hydrochloride and Formulation Thereof

ABSTRACT

Disclosed herein is an improved process for preparation of Sevelamer hydrochloride having phosphate binding capacity of 4.7 to 6.4 mmol/g. Further, the invention discloses Sevelamer hydrochloride compositions and a novel process for preparation of said compositions comprising high shear non-aqueous granulation.

RELATED APPLICATION

This application is a continuation of co-pending application Ser. No.12/377,129, filed 11 Feb. 2009, which in turn claims priority from U.S.National Stage entry of PCT Application Serial No. PCT/IN2007/000387,filed 31 Aug. 2007, which in turn claims priority from India Nationalapplication serial no. 1402/MUM/2006, filed 1 Sep. 2006, the contents ofwhich are incorporated by reference here.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to industrial process for preparation ofSevelamer hydrochloride. More specifically, the invention relates toimproved process for crosslinking of polyallylamine hydrochloridedispersed in an organic medium with epichlorohydrin to obtain Sevelamerhydrochloride having phosphate binding capacity of 4.7 to 6.4 mmol/g.

The present invention further relates to pharmaceutical compositions ofSevelamer hydrochloride and a novel process for preparation of saidcompositions comprising high shear non-aqueous granulation.

BACKGROUND AND PRIOR ART

Sevelamer hydrochloride is poly(allylamine hydrochloride) crosslinkedwith epichlorohydrin in which 40% of the amines are protonated.Sevelamer is chemically known aspoly(allylamine-co-N,N-diallyl-1,3-diamino-2-hydroxypropane)hydrochloride. Sevelamer hydrochloride is hydrophilic and swells, but isinsoluble in water. The structure is represented below

Sevelamer hydrochloride binds phosphate in the gastrointestinal tract tofacilitate phosphorus excretion in feces, thereby inhibiting phosphorusabsorption from the gut, and lowering the plasma phosphorusconcentration. Patients with end-stage renal disease (ESRD) retainphosphate which lead to development of hyperphosphatemia. Phosphoruscontrol is a primary goal in the care of patients with ESRD. Sevelamerhydrochloride which is a calcium-free, aluminium-free phosphate binder,allows physicians to control serum phosphorus in patients with ESRD whoare on hemodialysis, without increasing serum calcium levels orcontributing an excess calcium load. Clinical studies have shown thatSevelamer provides sustained reduction in markers of soft-tissue andcardiac calcification, such as serum calcium and phosphorusconcentrations and parathyroid hormone and also improves blood lipidprofiles. Thus, Sevelamer hydrochloride offers the promise of favourablyimpacting cardiac calcification and thereby reducing patient morbidityand mortality. Sevelamer hydrochloride taken with meals has been shownto decrease serum phosphorus concentrations in patients with ESRD whoare on hemodialysis. Treatment of hyperphosphatemia includes reductionin dietary intake of phosphate, inhibition of intestinal phosphateabsorption with phosphate binders and removal of phosphate withdialysis. Sevelamer hydrochloride treatment results in lowering oflow-density lipoprotein (LDL) and total serum cholesterol levels.Sevelamer hydrochloride is indicated for the control of serum phosphorusin patients with Chronic Kidney Disease (CKD) on hemodialysis andcontraindicated in patients with hypophosphatemia or bowel obstruction(www.fda.gov/cder/foi/labe1/2000/211791b1.pdf). In hemodialysispatients, Sevelamer hydrochloride decreases the incidence ofhypercalcemic episodes relative to patients on calcium treatment.

Sevelamer hydrochloride is marketed by Genzyme Corporation as Renagel®400 mg and Renagel® 800 mg tablets. Renagel® contains hypromellose,diacetylated monoglyceride, colloidal silicon dioxide, and stearic acidas inactive ingredients.

U.S. Pat. No. 5,496,545 discloses a method of removing phosphate from apatient by ion exchange, which involves oral administration of atherapeutically effective amount of a composition containing at leastone phosphate-binding polymer that is non-toxic and stable onceingested. The polymers are orally administered, and are useful for thetreatment of hyperphosphatemia. It also discloses spectrophotometricphosphate assay (PA) method to determine phosphate binding capacity(PBC) of crosslinked polyallylamine polymers. The PA value of Sevelamerhydrochloride obtained is 3.1 meq/g. It is also disclosed that it isdesirous to have higher PA for better activity.

J. R. Mazzeo et al in J. Pharm. Biomed. Anal. 19 (1999) 911-915 teachesHPLC Ion Chromatography PA method for the determination of PBC(phosphate binding capacity) of Sevelamer hydrochloride. The average PAof three Sevelamer hydrochloride batches reported is 5.8 mmol/g.

Commercially available Renagel samples, when tested by the HPLC ICmethod was found to have PA about 5.3 mmol/g, chloride content of about4.8 meq/g and degree of crosslinking in the range of 10% to 19%. Themarketed product had remarkable consistency in its PBC but lackedconsistency in its degree of cross linking.

U.S. Pat. No. 4,605,701 discloses process for preparing a cross-linkedmonoallylamine polymer. The method involves partially neutralizingpolyallylamine hydrochloride followed by addition of epichlorohydrin andhomogenization.

Further, the suspension obtained was dispersed into a liquid medium thatis immiscible with the aqueous solvent in presence of Silvan S-83.However, the said patent does not deal with the properties andapplications of the said polymer in phosphate binding.

WO 2006/097942 discloses biphasic process for crosslinking partlyneutralized aqueous Polyallylamine hydrochloride using a crosslinkingagent in a hydrocarbon solvent in presence of a dispersing agent to geta crosslinked polymer having a desired particle size range (60-100mesh). The process is carried out in such a manner that aqueous solutionis partly neutralized with alkali, mixed with crosslinking agent andcharged to an organic phase containing dispersing agent. Crosslinking iscarried out at a higher temperature and at a high speed of 800 to 1200rpm. The crosslinked polymer is then isolated by filtration, followed bywater washing to remove salts, followed by isopropyl alcohol (IPA)washing to remove water from the crosslinked polymer and finally dryingin a stationary tray dryer.

U.S. Pat. No. 6,525,113 describes process for preparing crosslinkedpolyallylamine by mixing polyallylamine, water, a hydroxide or alkoxideand a water miscible organic solvent or co-solvent such as acetonitrilefollowed by the addition of crosslinking agent.

These processes disclosed in above prior arts have drawbacks which areas follows:

-   -   (a) Mixing of epichlorohydrin with aqueous solution of partially        neutralised Polyallylamine hydrochloride is potentially a risky        operation on a large scale because the crosslinking commences        immediately upon mixing, which will eventually lead to gelling        and pose problems in adding thus thickened gel to the organic        phase on a large scale.    -   (b) The process is carried out at high speed of 800 to 1200 rpm.    -   (c) Recovery of water miscible solvents like acetonitrile is        difficult thus making the process uneconomical and unsuitable on        industrial scale.    -   (d) Washing with methanol or isopropylalcohol (IPA) generates        excess of organic effluent, which increases the cost of goods        and overheads.    -   (e) Methanol or IPA is extremely difficult to remove from the        crosslinked polymer. Since Sevelamer hydrochloride is an Active        Pharmaceutical Ingredient (API), it has to comply stringent ICH        guidelines for Organic Volatile Impurities (OVI). Methanol being        class II solvent as per the ICH guidelines is allowed maximum of        2000 ppm (0.2%) limit in API. IPA being class III solvent as per        the ICH guidelines is allowed maximum of 5000 ppm (0.5%) limit        in API. In the desired crosslinked polymer, IPA content is found        much above 5000 ppm. The prescribed ICH limit is very stringent        and difficult to achieve.    -   (f) Drying in stationary tray dryer imparts dark yellow colour        to the polymer which remains unchanged even after swelling with        water.    -   (g) The prior art processes are not amenable to large scale        manufacture, cannot give the desired quality and are        uneconomical. Thus there exists a need to develop an        economically viable manufacturing process which is amenable to        scale up and gives Sevelamer hydrochloride of superior quality.

Thus there is a need to develop a process for preparing Sevelamerhydrochloride with desired phosphate binding capacity, which simplifiesthe manufacturing method, minimizes the need for specialized equipments,brings down the need for wash solvents thereby bringing down themanufacturing costs. The present invention provides an economicallyviable process for preparation of Sevelamer hydrochloride suitable forindustrial scale up.

EP0997148 by Chugai Pharmaceuticals discloses tablets which containsphosphate-binding polymers having an average particle size of 400microns or less and 90% of particles are less than 500 microns andcontains crystalline cellulose and/or hydroxypropylcellulose with lowdegree substitution. Tablets show a moisture content of 1 to 14%.

W00128527 discloses a tablet core which comprises at least about 95% byweight of an aliphatic amine polymer and a process of producing thetablet by hydrating the aliphatic amine polymer to the desired moisturelevel; blending the aliphatic amine polymer with the excipients inamounts such that the polymer comprises at least about 95% by weight ofthe resulting blend; and compressing the blend to form tablet core.Tablet is coated with a water based coating.

W002085378 discloses a composition comprising a stable polyallylaminehydrochloride polymer wherein about 4% to about 12% by weight of thepolymer is a chloride anion.

EP1153940 discloses phosphate binding polymer having a true specificgravity of 1.18-1.24 and process for producing phosphate binding polymertablets.

Prior art discloses various formulations of Sevelamer by methodsinvolving direct compression or dry granulation. However, the prior artfurther states that tableting of phosphate binding polymer Sevelamer bywet granulation is impossible and is difficult to achieve.

The inventors of the present invention tried out several ways forformulating Sevelamer hydrochloride and have successfully developedformulations by high shear non-aqueous granulation which providesimproved cohesiveness of particles, excellent flowability andcompression characteristics.

OBJECT OF THE INVENTION

The main object of the present invention is to provide industrialprocess for preparation of Sevelamer hydrochloride having PA in therange of about 4.7 mmol/g to about 6.4 mmol/g and chloride content inthe range of about 3.74 to about 5.60 meq/g.

Another object of the invention is to provide pharmaceuticalcompositions comprising a therapeutically effective amount of Sevelamerhydrochloride along with suitable pharmaceutically acceptableexcipients.

Another object of the invention is to provide a novel process forpreparation of Sevelamer hydrochloride compositions comprising highshear non-aqueous granulation.

Another object of the invention is to provide improved and simplifiedprocess for preparation of Sevelamer hydrochloride which will eliminatethe use of acetonitrile and the risk of gelling also avoid use of IPAfor removing water.

Another object of the invention is to provide Sevelamer hydrochloridewhich will meet the stringent ICH (International Committee ofHarmonisation) requirements.

Yet another object of the invention is to provide process which yieldsSevelamer hydrochloride having consistency in degree of cross linkingand avoids the need of specialized equipments for the manufacture of thesaid product and thereby reducing the manufacturing cost.

Still another object of the invention is to provide compositions for thecontrol of serum phosphorus in patients with Chronic Kidney Disease(CKD) on hemodialysis.

Another object of the invention is to provide method for reducing theserum phosphorus in patients with Chronic Kidney Disease (CKD) onhemodialysis comprising administering a therapeutically effective amountof Sevelamer hydrochloride along with suitable pharmaceuticallyacceptable excipients.

SUMMARY OF THE INVENTION

The present invention discloses industrial process for preparation ofSevelamer hydrochloride having phosphate binding capacity of 4.7 to 6.4mmol/g comprising the steps of

-   -   (a) dissolving polyallylamine hydrochloride in water to obtain        an aqueous solution;    -   (b) partially neutralizing the aqueous solution of        polyallylamine hydrochloride with 65 to 70 mole % of alkali with        respect to polyallylamine hydrochloride;    -   (c) charging dispersing agent to hydrocarbon solvent to obtain        solution;    -   (d) mixing partially neutralized aqueous polyallylamine        hydrochloride solution with the solution obtained in step (c);    -   (e) stirring the obtained reaction mixture at speed of about 40        to about 250 revolutions per minute to get fine dispersion of        aqueous phase in organic phase;    -   (f) heating the suspension obtained in step (e) at an elevated        temperature;    -   (g) charging 5 to 12% by weight of epichlorohydrin in relation        to polyallylamine hydrochloride to the suspension of step (0        maintaining an elevated temperature till cross linking is        complete;    -   (h) cooling the reaction mixture at temperature of 25 to 35° C.        and isolating the compound by washing the obtained cake with        water;    -   (i) drying the wet cake in a Fluidized Bed Dryer at temperature        of about 25 to 90° C. to get Sevelamer hydrochloride with        phosphate binding capacity of 4.7 to 6.4 mmol/gm.

In another aspect of the invention polyallylamine hydrochloride isprepared by reacting allylamine with hydrochloric acid to get allylaminehydrochloride salt and polymerising the obtained allylaminehydrochloride salt in presence of2,2′-Azobis[2-methyl-N-(2-hydroxyethyl)propionamide (VA-086), a freeradical initiator to get polyallylamine hydrochloride. Thepolyallylamine hydrochloride is having intrinsic viscosity of 0.14 to0.22 decilitre/gm.

The present invention further discloses pharmaceutical compositionscomprising a therapeutically effective amount of Sevelamer hydrochloridealong with suitable pharmaceutically acceptable excipients. Saidcompositions are used in the control of serum phosphorus in patientssuffering from chronic kidney disease (CKD) on hemodialysis. Further,the invention discloses a novel process for preparation of Sevelamerhydrochloride compositions comprising high shear non-aqueousgranulation.

According to the present invention, the process for preparation ofSevelamer hydrochloride compositions comprising high shear non-aqueousgranulation comprises the steps of:

-   -   (a) preparing a mixture of Sevelamer hydrochloride and one or        more diluents;    -   (b) optionally wetting the mixture;    -   (c) preparing a non-aqueous binder solution by dissolving binder        in an organic solvent;    -   (d) granulating the mixture of step (a) or step (b) using        non-aqueous binder solution by high shear non-aqueous        granulation to form granulated mass;    -   (e) drying the granulated mass;    -   (f) milling the dried mass using ball mill or fluid energy mill        to form granules of suitable size;    -   (g) lubricating the milled granules;    -   (h) compressing the lubricated granules into tablets or filling        the lubricated granules into capsules;    -   (i) coating the compressed tablets.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows powder ′³C NMR of Renagel tablet

FIG. 2 shows powder ′³C NMR of Renagel tablet

FIG. 3 shows powder ′³C NMR of Renagel tablet

FIG. 4 shows powder ¹³C NMR of Renagel tablet

FIG. 5 shows powder ¹³C NMR of Sevelamer hydrochloride (API) obtained byfollowing IPA wash-tray drying method.

FIG. 6 shows powder ′³C NMR of Sevelamer hydrochloride (API) obtained byfollowing IPA wash-tray drying method.

FIG. 7 shows powder ′³C NMR of Sevelamer hydrochloride (API) obtained byfollowing IPA wash-tray drying method.

FIG. 8 shows powder ′³C NMR of Sevelamer hydrochloride (API) obtained byfollowing water wash-FBD method.

FIG. 9 shows powder ′³C NMR of Sevelamer hydrochloride (API) obtained byfollowing water wash-FBD method.

FIG. 10 shows powder ′³C NMR of Sevelamer hydrochloride (API) obtainedby following water wash-FBD method:

FIG. 11 shows powder ¹³C NMR of Sevelamer hydrochloride (API) obtainedby the present process.

FIG. 12 shows powder ′³C NMR of Sevelamer hydrochloride (API) obtainedby the present process.

FIG. 13 shows powder ¹³C NMR of Sevelamer hydrochloride (API) obtainedby the present process.

FIG. 14 shows powder ′³C NMR of Sevelamer hydrochloride (API) obtainedby the present process.

FIG. 15 shows shape of particles of Sevelamer hydrochloride (API) viewedthrough a microscope at a magnification of 40×.

DETAILED DESCRIPTION OF THE INVENTION

The present invention describes an industrial process for thepreparation of Sevelamer hydrochloride. The present invention furtherinvolves improved process for crosslinking polyallylamine hydrochloridedispersed in an organic medium with epichlorohydrin to obtain Sevelamerhydrochloride having phosphate binding capacity of 4.7 to 6.4 mmol/g.

The present invention further describes pharmaceutical compositionscomprising a therapeutically effective amount of Sevelamer hydrochloridealong with suitable pharmaceutically acceptable excipients. A novelprocess for preparation of said Sevelamer hydrochloride compositionscomprising high shear non-aqueous granulation is also described.

According to one embodiment of the invention process for preparation ofSevelamer hydrochloride according to the invention comprises the stepsof;

-   -   (a) dissolving polyallylamine hydrochloride in water to obtain        an aqueous solution;    -   (b) partially neutralizing the aqueous solution of        polyallylamine hydrochloride with 65 to 70 mole % of alkali with        respect to polyallylamine hydrochloride;    -   (c) charging dispersing agent to hydrocarbon solvent to obtain        solution;    -   (d) mixing partially neutralized aqueous polyallylamine        hydrochloride solution with the solution obtained in step (c);    -   (e) stirring the obtained reaction mixture at speed of about 40        to about 250 revolutions per minute to get fine dispersion of        aqueous phase in organic phase;    -   (f) heating the suspension obtained in step (e) at an elevated        temperature;    -   (g) charging 5 to 12% by weight of epichlorohydrin with respect        to polyallylamine hydrochloride to the suspension of step (f)        maintaining an elevated temperature till cross linking is        complete;    -   (h) cooling the reaction mixture at temperature of 25 to 35° C.        and isolating the compound by washing the obtained cake with        water and filtration;    -   (i) drying the wet cake in a Fluidized Bed Dryer at temperature        of about 25 to 90° C. to get Sevelamer hydrochloride with        phosphate binding capacity of 4.7 to 6.4 mmol/gm.

In another embodiment of the invention polyallylamine hydrochloride isprepared by reacting allylamine with hydrochloric acid to get allylaminehydrochloride salt and polymerising the obtained allylaminehydrochloride salt in presence of (VA-086), a free radical initiator toget polyallylamine hydrochloride. The polyallylamine hydrochloride ishaving intrinsic viscosity of 0.14 to 0.22 decilitre/g.

According to the present invention polyallylamine hydrochloride isdissolved in water to obtain an aqueous solution of polyallylaminehydrochloride.

According to another embodiment of the present invention the aqueoussolution polyallylamine hydrochloride is partially neutralized withalkali.

According to another embodiment of the invention alkali used is alkalimetal hydroxide preferably sodium hydroxide.

In another embodiment of the present invention partial neutralization iscarried out by adding 65 to 70 mole % of alkali with respect topolyallylamine hydrochloride, either as a solid or a solution. Moles ofpolyallylamine hydrochloride is calculated by dividing the weight ofpolyallylamine hydrochloride taken for reaction with molecular weight ofallylamine hydrochloride. Using alkali in this range provides thechloride content in the desired range of about 4.3 to about 5.3 meq/g.

According to another embodiment of the present invention the dispersingagent is charged in hydrocarbon solvent.

According to yet another embodiment, the dispersing agent is selectedfrom trioleate surfactants, preferably sorbitan trioleate (SPAN-85).

In another embodiment of the present invention, hydrocarbon solvent isselected

from aliphatic or aromatic hydrocarbons preferably, aromatichydrocarbons.

According to another embodiment of the present invention aromatichydrocarbon is selected from benzene, toluene, xylenes, chlorobenzenes,nitrobenzenes or mixtures thereof.

In yet another embodiment of the present invention partially neutralizedaqueous polyallylamine hydrochloride is mixed with hydrocarbon solventcontaining dispersing agent in a conventional reactor and stirred atspeed of about 40 to about 250 revolutions per minutes (RPM) to get finedispersion of aqueous phase in organic phase followed by heating thesuspension obtained at elevated temperature.

According to another embodiment of the present invention the speed forstirring the reaction mixture ranges from about 40 to about 250revolutions per minute, preferably 40 to 60 revolutions per minute.

In another embodiment of the present invention elevated temperatureranges from about 40° C. to about 150° C., preferably 55 to 60° C.

In another embodiment of the present invention epichlorohydrin ischarged at elevated temperature and maintaining the same temperaturetill cross linking is complete followed by cooling and isolating thecake of crosslinked polymer.

According to another embodiment of the present invention epichlorohydrinis used in the range of 5% to 12% by weight as compared to the weight ofpolyallylamine hydrochloride, preferably 6 to 9% by weight. Usingepichlorohydrin in this range provides the PBC in the desired range ofabout 4.7 to 6.4 mmol/g. Using less than 5% quantity of epichlorohydrinresults in a sticky. cross linked polymer and very poor yield due towater solubility, whereas using more than 12% quantity ofepichlorohydrin lowers the PBC below 5.3 mmol/g.

In yet another embodiment of the invention, cooling is carried out bylowering the temperature to ambient temperature, preferably 25 to 35° C.and isolation is carried out by nutsching under suction or centrifuging,preferably centrifuging.

In another embodiment the obtained cake of crosslinked polymer is washedwith water to remove sodium chloride salt and dried in Fluidized BedDryer (FBD) at temperature of about 25 to 90° C.; preferably attemperature range of 40° C. to 60° C. to get Sevelamer hydrochloridehaving phosphate binding capacity in the range 4.7 to 6.4 mmol/g.

The preparation of Sevelamer hydrochloride having phosphate bindingcapacity of 4.7 to 6.4 mmol/g is one of the important features of thepresent invention.

Elimination of IPA from the final isolation stage for removing wateraccording to the present invention has a surprising effect on thephysical property like appearance, swellability etc. of the cross linkedpolyallylamine. Another surprising effect of the process according tothe present invention is that Sevelamer hydrochloride is obtained hashigher PBC than that obtained by following an identical experimentcarried out using IPA for water removal.

In a preferred embodiment of the invention, polyallylamine hydrochlorideand water are mixed at 25 to 35° C. to get a clear solution. Thesolution is further cooled to 5 to 15° C. and aqueous solution of alkali(65-70 mole % by weight of polyallylamine hydrochloride) is added to thereaction mass at 5 to 15° C. and stirred for 30 minutes. Dispersingagent in hydrocarbon solvent is added to the obtained reaction mixtureat 5 to 15° C. The temperature of the reaction mixture is then raised to20 to 25° C. and maintained for 15 min. The reaction mixture is filteredto remove any extraneous matter at 25 to 35° C. and temperature of theobtained solution is further raised to 55 to 60° C. and maintained for15 minutes. Epichlorohydrin (5-12% by weight of polyallylaminehydrochloride) is added to reaction mixture at constant temperature of55 to 60° C. The reaction mixture is then cooled to 25 to 35′C andproduct is isolated by centrifugation. The wet cake is further sludgedwith water for 45 min. at 25 to 50° C. and filtered, then dried in FBDat 25 to 90° C.

Crosslinked polymer Sevelamer hydrochloride obtained by the processaccording to the invention is having chloride content from about 3.74 toabout 5.6 meq/g, Phosphate Binding Capacity of about 4.7 to about 6.4mmol/g and the degree of crosslinking from about 12% to about 18%.

Preferably, the chloride content ranges from about 4.3 to about 5.3meq/g, Phosphate Binding Capacity of about 5.3 to about 6.0 mmol/gm andthe degree of crosslinking from about 12% to about 16%.

Sevelamer hydrochloride as prepared by the present process and testedfor PBC shows the following properties as below;

Karl Fischer<5% Loss on drying (LOD)<5%

The Sevelamer hydrochloride obtained by the present process is off-whitein color and also swells more when suspended in water as compared to theSevelamer hydrochloride obtained by following the process disclosed inWO 2006/097942. Capacity to swell more translates into higher PA by HPLCIC method which is shown in Table I below;

TABLE I Sevelamer Hydrochloride Phosphate binding capacity by IC method:Phosphate Epichloro- Sodium binding Batch hydrin hydroxide capacity Sr.No. no. % w/w % mole Method (mmol/g) 01 122 9.0 69.0 IPA wash-Tray 5.26drying 02 123 9.0 69.0 IPA wash-Tray 5.17 drying 03 130 9.0 69.0 Waterwash-FBD 5.51 04 131 9.0 69.0 Water wash-FBD 5.48 05 128 11.8 69.0 IPAwash-Tray 4.95 drying 06 121 11.8 69.0 Water wash-FBD 5.69

The process disclosed herewith also fulfills the objective of complyingwith ICH requirements. IPA contamination (peak 2) can be seen in thebatches with IPA wash and dried in Tray drier [FIG. 5 (Batch no. 86),FIG. 6 (Batch no. 87) and FIG. 7 (Batch no. 89)], whereas no IPAcontamination was observed in batches carried out with water wash anddried in FBD according to the present invention as shown in FIG. 8(Batch no. 130), FIG. 9 (Batch no. 131) and FIG. 10 (Batch no. 121).

Renagel tablets were analyzed by solid state ″C NMR technique. The areaunder the curve (AUC) of peaks 1 and 2 as shown in FIG. 1 (Batch no.644871), FIG. 2 (Batch no. 45273 B), FIG. 3 (Batch no. 63455) and FIG. 4(Batch no. 33685A) were determined by Powder ″C NMR technique. The sumtotal of AUC of peak 1 and 2 is termed as the degree of cross linking inpercentage.

The degree of crosslinking of Renagel formulation ranged from 10% to 19%(Table II). It was therefore desirable to produce Sevelamerhydrochloride having consistency in the degree of crosslinking. Theobject of the current invention is to produce the crosslinked polymerhaving degree of crosslinking in the range of 12% to 18%.

TABLE II % Chloride Sr. Batch % Sodium Content PBC Degree of No SampleNo. Epichlorohydrin Hydroxide meq/g mmol/g Crosslinking* 1 RENAGEL644871 — — 5.32 18.19 2 RENAGEL 45273 B — — 4.8 5.30 10.58 3 RENAGEL33685 A — — — 5.30 12.29 4 RENAGEL  63455 — — — 5.28 13.87 *degree ofcrosslinkmg is based on the ″C NMR recorded at National ChemicalLaboratory, Pune.

Thus the process disclosed herewith meets the primary objective ofmaking Sevelamer hydrochloride having chloride content from about 3.74to about 5.60 meq/g, Phosphate Binding Capacity of about 5.3 to about6.0 mmol/g and consistent degree of crosslinking from about 12% to about16% (Table III) as shown in FIG. 11 (Batch no. 99), FIG. 12 (Batch no.132), FIG. 13 (Batch no. 133) and FIG. 14 (Batch no. 134).

TABLE III % Chloride Sr. Batch Epichloro- % Sodium Content PBC Degree ofNo. No. hydrin Hydroxide meq/g mmol/g crosslinking* 1 99 6.79 65.5 4.805.39 13.80 2 132 6.79 65.5 4.79 5.44 13.21 3 133 6.79 65.5 4.64 5.5413.14 4 134 6.79 65.5 4.60 5.42 13.12 5 130 9.00 69.0 4.68 5.51 15.38 6131 9.00 69.0 4.47 5.48 15.39 *degree of crosslinking is based on the′³C NMR recorded at National Chemical Laboratory, Pune.

Sevelamer hydrochloride prepared by the process described by the presentinvention is used in formulating Sevelamer hydrochloride compositions.

Phosphate binding polymer Sevelamer is water insoluble but it swells incontact with water. Due to this tendency of swelling, formulatingSevelamer by aqueous granulation becomes difficult. Although attemptshave been made to formulate Sevelamer by wet granulation method, none ofthe prior art discloses a successful process for high shear non-aqueousgranulation being carried out in an equipment such as a high shear rapidmixer granulator or a planetary mixer.

Inventors of the present invention attempted granulation of Sevelamerhydrochloride using spray granulation technique. However, the resultswere not satisfactory since the binding solution containingethylcellulose dissolved in isopropyl alcohol was very viscous and posedproblem for uniform spraying of the granulating fluid on to the activeingredient and also the dry mass becomes tacky and forms sticky lumps.

Attempts were also made for preparation of Sevelamer hydrochloridecompositions by hot melt granulation and hot melt extrusion techniquesbut the results were not satisfactory as very high quantity of binderwas required and granules produced were lacking adequate flowproperties.

Although the prior art states that tableting of a phosphate bindingpolymer such as Sevelamer hydrochloride is impossible by wetgranulation, the inventors of the present invention have successfullydeveloped a novel process for granulation of Sevelamer hydrochloride byhigh shear non-aqueous granulation.

According to the present invention, the process for preparation ofSevelamer hydrochloride compositions comprising high shear non-aqueousgranulation comprises the steps of:

-   -   (a) preparing a mixture of Sevelamer hydrochloride and one or        more diluents;    -   (b) optionally wetting the prepared mixture;    -   (c) preparing a non-aqueous binder solution by dissolving binder        in an organic solvent;    -   (d) granulating the mixture of step (a) or step (b) with        non-aqueous binder solution by high shear non-aqueous        granulation to form granulated mass;    -   (e) drying the granulated mass;    -   (f) milling the dried mass using ball mill or fluid energy mill        to form granules of suitable size;    -   (g) lubricating the milled granules;    -   (h) compressing the lubricated granules into tablets or filling        the lubricated granules into capsules;    -   (i) coating the compressed tablets.

According to the invention, the particles of Sevelamer hydrochloride areround in shape, particularly spherical or oval in shape (ref. FIG. 15).Spherical or oval shaped particles of Sevelamer hydrochloride have lowbulk density and poor flowability and further resist size reduction.Particles resist deformation and do not rupture or fracture. Due tothese characteristics of Sevelamer hydrochloride, formulating Sevelamerhydrochloride by direct compression method becomes extremely difficult.In the practice of the present invention, although the sphericalmorphology and hydrophilic nature of active ingredient Sevelamerhydrochloride presents a special challenge to the formulator, theinventors of the present invention have successfully prepared Sevelamerhydrochloride compositions by high shear non-aqueous granulation and byusing rapid mixer granulator or planetary mixer.

According to one embodiment of the invention, the process of preparationof Sevelamer hydrochloride by high shear non-aqueous granulationcomprises providing a mixture of active ingredient Sevelamerhydrochloride and one or more diluents; wetting the said mixture usingpurified water; further granulating by non-aqueous granulation using anon-aqueous solvent and preferably by using a non-aqueous bindersolution prepared by dissolving the binder in an organic solvent; thegranulation process being carried out in a rapid mixer granulator.Granulated mass is dried. Dried mass is further milled or pulverized toget granules size less than 425 microns (40#) and preferably less than250 microns (60#) using a multi-mill initially and then a fluid energymill or a ball mill and preferably using a ball mill. Milled orpulverized granules are lubricated using lubricants known in the art andfurther compressed to provide tablets of required size. Compressedtablets are further film coated by non-aqueous coating or aqueouscoating or by hydroalcoholic coating.

According to a preferred embodiment, the process of preparation ofSevelamer hydrochloride compositions comprises mixing Sevelamerhydrochloride with one or more diluents; wetting the mixture using asolution of polyethylene glycol 6000 (Macrogol) dissolved in purifiedwater; preparing a non-aqueous binder solution by dissolving polyvinylpyrrolidone (Povidone K-30) in an organic solvent such as isopropylalcohol; further granulating using the said non-aqueous binder solutionand drying the granules. Sizing the dried granules through 60# onvibrosifter after milling with multi-mill and ball mill and furtherblending with commonly used lubricants and compressing the granules.Core tablets are further film coated by aqueous process till a weightgain of 4.0% to 6.0% is achieved.

Sevelamer hydrochloride is not a free flowing powder and is bulky.Wetting with purified water helps in decreasing the interparticulatedistance and increasing the contact area between the particles; thusmaking Sevelamer Hydrochloride more amenable for the non-aqueousgranulation. Wetting is carried out either in a rapid mixer granulatoror a planetary mixer. In the practice of the present invention, wettingof mixture of active and diluent is carried out using about 2% to 9% byweight of purified water. Alternatively, the mixture of active anddiluent may be made wet using a solution of polyethylene glycoldissolved in purified water. In an alternate method, polyethylene glycol6000 may be added into the dry mix as a fine powder during the mixingstep. Polyethylene glycols of various grades may be used such aspolyethylene glycol 6000 or the like.

In the practice of the present invention, non-aqueous granulation iscarried out by adding the binder slowly in a thin stream continuouslyusing a peristaltic pump under high speed mixing with the impeller ‘on’and chopper ‘off’. On completion of binder addition, mixing is continuedat high impeller speed till cohesive granular mass is obtained. If themass is lumpy then chopper may be used at high speed with impeller alsoat high speed to obtain uniform wet mass.

High shear non-aqueous granulation as practiced by the present inventionimproves the cohesiveness of particles and provides excellentflowability and compression characteristics to the tablet. As thegranules exhibit good flow properties, tablets produced possessuniformity in weight.

Drying of granulated mass may be carried out using fluidized bed drieror tray drier. Initial drying is performed without application oftemperature and further the granulated mass is dried for sufficient timeat about 45° C. to 50° C. till loss on drying value is achieved in therange of about 8.0% to about 10.0% when about 9.0% water is used or alower loss on drying value considering the amount of water used forwetting. If planetary mixer is used for granulation, the wet mass is tobe milled on a multi-mill using 8.0 mm screen and then charged fordrying.

According to a preferred embodiment, the process comprises mixingSevelamer hydrochloride with one or more diluents; optionally wettingthe mixture using purified water in a rapid mixer granulator; preparinga non-aqueous binder solution by dissolving ethyl cellulose in anorganic solvent such as isopropyl alcohol; granulating the mixture ofSevelamer hydrochloride and diluents using the said non-aqueous bindersolution and drying the granules. Sizing the dried granules through 60#on vibrosifter after milling initially with multi-mill and further withball mill and further blending with commonly used lubricants andcompressing the granules. Core tablets are further film coated.

According to a more preferred embodiment, Sevelamer hydrochloride ismixed with mannitol and made wet using purified water; granulated usingnon-aqueous binder solution prepared by dissolving ethyl cellulose inisopropyl alcohol. Granulation is carried out in a rapid mixergranulator and the granulated mass is dried till loss on drying of about9.0% is achieved. Dried mass is sized using ball, mill to achievegranules of required size; lubricated using lubricants and compressedinto tablets or filled into capsules.

According to another embodiment of the invention, the process ofpreparation of Sevelamer hydrochloride composition comprises providing amixture of active ingredient Sevelamer hydrochloride and one or moreexcipients; granulating the mixture by high shear non-aqueousgranulation using a non-aqueous solvent and preferably by using anon-aqueous binder solution prepared by dissolving the binder in thenon-aqueous solvent; the granulation process being carried out in arapid mixer granulator. Granulated mass is further dried and a loss ondrying value in the range of about 3.0% to 5.0% (which is similar toloss on drying of active Sevelamer hydrochloride) is achieved. Driedgranules are further milled or pulverized to get granules size of 425microns (40#) and preferably less than 250 microns (60#) using a fluidenergy mill or a ball mill and preferably by using a ball mill. Milledor pulverized granules are lubricated using lubricants known in the artand further compressed to provide tablets of required size or filledinto capsules. Compressed tablets may be further coated.

According to one embodiment, the granules provided by high shearnon-aqueous granulation process as described herein are sphericalgranules of size less than 425 microns, preferably less than 250microns. Although the dried mass can be milled or pulverized usingconventional equipments known in the art such as a multimill, co-mill,cadmill or fitzmill, they have limitations when used for size reductionof Sevelamer hydrochloride granules. Granule size below 425 microns(which passes through 40#) is difficult to obtain using conventionalmills. Large granules pose difficulties during compression by decreasingthe compressibility of the granules and produces porous tablets with lowhardness which consequently exhibit high friability and pose a risk ofmoisture uptake during aqueous film coating. Oversized granules retainedafter milling through 0.5 mm screen on a conventional mill and siftingon a vibrosifter through 60# are milled in a ball mill or fluidizedenergy mill to obtain a granule size below 425 microns, preferably below250 microns.

According to the invention, size reduction or pulverization using fluidenergy mill or ball mill provides spherical granules of size less than250 microns, which provides an ease in compressibility. Ball millingbeing the preferred mode for size reduction of granules. In ballmilling, the process of size reduction occurs due to combined effect ofimpact and attrition. In a Fluid energy mill, the material is suspendedand conveyed at high velocity by air, which is passed through nozzles at100 to 150 pounds per square inch. The violent turbulence of the airreduces the particle size by interparticulate attrition. Ball mill ispreferred in terms of output and productivity for large scale batches.

Milled mass is further sifted through a vibrosifter and oversizedgranules are milled through a mill preferably a ball mill with stainlesssteel balls and further sifted through a vibrosifter. Mass is milledwith ball mill and sifted through vibrosifter till the resultantgranules passed through 60#. According to a preferred aspect, granulesof the present invention preferably have a granule size of 100% passingthrough 60# or 40#. Granule size of 250 microns or less providesatisfactory compression of granules and further provides elegantnon-porous, non-friable tablets with a smooth impervious surface whichcan withstand the rigours of aqueous film coating.

In the practice of the present invention, the granule size is controlledsuch that 100% granules passes through 60# and provides tablets whichexhibit a smooth impervious surface with a hardness greater than 100 N,friability less than 0.8%, preferably in the range of 0 to 0.1% anddisintegration time of about 5 minutes, and a smooth aqueous filmcoating operation. By controlling the granule size at less than 425microns (which passes through 40#) and preferably less than 250 microns(which passes through 60#), elegant tablets are produced.

In a preferred embodiment, coating of tablets is done using an aqueouscoating method. Aqueous coating of an hydrophilic active ingredient isanother difficult process and posed a real challenge to the inventors ofthe present invention as the Sevelamer hydrochloride has a tendency toswell in presence of water. Aqueous coating has been achieved by havinga fine control on the hardness of the cores, which balances the need fora hard core to ensure good coating as well as meets the requirement fordisintegration of coated tablets. As the tablet core is hard with animpervious smooth surface, it withstands the aqueous film coating andthe polymer Sevelamer hydrochloride does not swell during coating.

Film coating may be carried out using polymers such as polyvinylalcohol, hydroxyethyl cellulose, ethylcellulose, hydroxypropyl methylcellulose, methacrylicacid co-polymers. Ready mix coating materials maycomprise plasticizers selected from propylene glycol, triacetin orpolyethylene glycol. Coating agents may be used in the range of about3.0% to about 8.0% by weight of total composition.

Tablets may be compressed using suitable punches and dies. Tablets maybe of oval, elliptical, spherical or caplet shape. Compression can becarried out using equipments known in the art such as a rotary tabletpress. Tablets prepared by the process according to the invention meetthe specification for disintegration (Limit not more than 30 minutes).Other parameters of tablets such as hardness, friability, and thickness,were measured and the results met the prerequisites of establishedacceptance criteria.

Compositions of Sevelamer Hydrochloride, particularly the tablets may bepacked in aluminium strips or by cold formed blister pack, which is acold process of blister packing, which acts as an excellent moisturebarrier with negligible moisture vapor transmission rate and adequateenvironmental protection during shelf life. Tablet or capsulecompositions may also be bulk packed optionally with a dessicant.

According to another embodiment, the spherical granules produced by thehigh shear non-aqueous granulation process may be filled along withsuitable excipients into hard gelatin capsules of suitable size. Capsulefilling can be done using a suitable capsule filling machine.

The present invention further provides pharmaceutical compositionscomprising a therapeutically effective amount of Sevelamer hydrochloridealong with suitable pharmaceutically acceptable excipients. Saidcompositions are used in the control of serum phosphorus in patientssuffering from chronic kidney disease (CKD) on hemodialysis.

According to one embodiment, the compositions of the present inventioncomprises the active ingredient Sevelamer hydrochloride in the range ofabout 66.0% to about 80.0% by weight of total composition. Moreparticularly, Sevelamer hydrochloride compositions of the presentinvention may be provided in dose strength of 400 mg and 800 mg whichare scaleup/scaledown formulations.

According, to a preferred embodiment, the compositions contain about66.0% to about 80.0% by weight of Sevelamer hydrochloride, about 5.0% toabout 21.0% by weight of diluent, about 3.0% to about 15.0% by weight ofbinder, about 0.10% to about 3.0% by weight of glidant, about 0.10% toabout 3.0% by weight of lubricants and about 3.0% to about 8.0% byweight of coating agents.

According to another preferred embodiment, the compositions contain70.0% to 72.0% by weight of Sevelamer hydrochloride, 7.0% to 10.0% byweight of mannitol, 7.35% to 7.5% by weight of ethyl cellulose, 0.25% to0.3% by weight of colloidal silicon dioxide, 0.25% to 0.3% by weight oflubricants and 5.0% to 6.0% by weight of coating agents.

According to yet another preferred embodiment, the compositions contain75.0% to 78.0% by weight of Sevelamer hydrochloride, 7.0% to 10.0% byweight of mannitol, 7.35% to 8.0% by weight of ethyl cellulose, 0.6% to0.9% by weight of colloidal silicon dioxide, 0.6% to 0.9% by weight oflubricants and 5.0% to 6.0% by weight of coating agents.

Compositions of present invention may include one or morepharmaceutically acceptable excipients selected from diluents, binders,lubricants, glidants, colorants, coating agents, plasticizers and thelike.

Diluents are substances which usually provide bulk to the composition.Diluents which can be used for preparation of Sevelamer hydrochloridecompositions as per the invention include, but are not limited to maizestarch, microcrystalline cellulose of various grades like Avicel PH 101,112, 102, pregelatinized starch, mannitol, calcium carbonate, calciumsulfate and the like. Mannitol being the preferred diluent. Diluents maybe used in the range of about 5% to about 21% by weight of totalcomposition.

Tablet compositions which uses lactose and dextrose as diluents showdiscoloration as the tablets turn to yellowish brown colour due toMaillard reaction. As diabetes is the leading cause of end-stage renaldisease (ESRD) in many cases, the use of sugars as diluents is avoided.Similarly dibasic calcium phosphate, tribasic calcium phosphate are alsoavoided since Sevelamer is a phosphate binding polymer and any phosphatecontaining diluent may compete for phosphate binding activity ofSevelamer.

Considering the end use of the formulation, mannitol is the preferreddiluent. On oral administration, mannitol is not absorbed significantlyfrom the gastrointestinal tract. Mannitol is used in direct compressiontablet applications or in wet granulation. Granulations containingmannitol have the advantage of being dried easily. Sevelamerhydrochloride being moisture sensitive, mannitol is the preferreddiluent as it is not hygroscopic. Various grades of mannitol areavailable commercially. Preferred grades of mannitol include PearlitolSD 200 of Roquette, France.

Binders impart cohesiveness to tablet formulation and ensures that thetablet remain intact after compression. Binders which can be used forpreparation of Sevelamer hydrochloride compositions as per the inventioninclude, but are not limited to hydroxy propyl methyl cellulose, hydroxypropyl cellulose, hydroxy ethyl cellulose, ethyl cellulose, othercellulose derivatives, maize starch, polyvinylpyrrolidone alone or incombination with polyethylene glycols and the like. Binders may be usedin the range of about 3.0% to about 15.0% by weight of totalcomposition. Binder preferred in the practice of the present inventionis ethyl cellulose and polyvinyl pyrrolidone with polyethylene glycol6000.

Different grades of ethyl cellulose having various viscosities arecommercially available. Ethyl cellulose of specific grades or blends ofdifferent grades may be used to obtain solutions of desired viscosity.Ethyl cellulose having viscosity in the range of 4 cps to 22 cps isused; preferred being ethycellulose with viscosity of about 5 to 15 cps.The preferred grade of ethylcellulose used for Sevelamer: hydrochloridetablets is Ethocel EC-N 7 Pharm manufactured by Dow chemical company.Ethyl cellulose is not metabolized following oral consumption andtherefore a non-calorific substance.

Lubricants which can be used for preparation of Sevelamer hydrochloridecompositions as per the invention include, but are not limited tostearic acid, calcium stearate, glyceryl monostearate, glycerylpalmitostearate, zinc stearate, magnesium stearate, sodium stearylfumarate, calcium stearyl fumarate, hydrogenated vegetable oil, mineraloil, polyethylene glycol, sodium lauryl sulphate, and the like. Glidantswhich can be used include colloidal silicon dioxide, talc and the like.Lubricants and glidants may be used in the range of about 0.1% to about3.0% by weight of total composition.

According to another embodiment of the invention, the active ingredientSevelamer hydrochloride used in the composition possess a phosphatebinding capacity of about 4.7 mmol/gm to about 6.4 mmol/gm.

Composition prepared by the process as described herein has a loss ondrying value of about 3% to about 12%, particularly about 7% to about9%.

Although the present invention makes use of organic solvents such asisopropyl alcohol for non-aqueous granulation, the organic volatileimpurity level in the finished product is quite low and is within thepermissible limit. (Limit as per ICH guidelines: 5000 ppm)

Compositions prepared by the novel process as described here withstandthe accelerated stability conditions of temperature and relativehumidity and maintain their physical and chemical integrity ataccelerated conditions of stability.

The present invention further provides use of the compositions ofSevelamer hydrochloride in the control of serum phosphorus in patientssuffering from chronic kidney disease (CKD) on hemodialysis.

According to one embodiment, the present invention provides a method fortreating a patient suffering from chronic kidney disease (CKD) onhemodialysis comprising administering a therapeutically effective amountof Sevelamer hydrochloride composition.

As used herein, the term “therapeutically effective amount” refers to anamount sufficient to cause an improvement in a clinically significantcondition in the patient or even prevent a disease, disorder orcondition in a patient.

As used herein, the term “excipient” refers to a pharmaceuticallyacceptable ingredient that is commonly used in the pharmaceuticaltechnology for preparing granulate and/or solid oral dosageformulations.

As used herein, the term “tablet” is intended to encompass compressedpharmaceutical dosage formulations of all shapes and sizes, whethercoated or uncoated.

The present invention is further illustrated by reference to thefollowing examples which does not limit the scope of the invention inany way. It will be apparent to those skilled in the art that manymodifications, both to the materials and methods, can be practicedwithout departing from the purpose and scope of the disclosure.

EXAMPLES Example 1 Preparation of Polyallylamine Hydrochloride

Allylamine (75 g) was added to hydrochloric acid (134.2 g) bymaintaining the temperature 5 to 15° C. The pH was adjusted to 1 to 2and the solution was stirred for 30 min. The recovery of acidic water attemp below 90° C. was carried out under vacuum to get allylaminehydrochloride salt and the recovery till approx. about 1 volume of waterbased on input allylamine was distilled out to get thick mass. Thereaction mass was cooled to 25 to 35° C. and water was added to getuniform slurry and the reaction mass was heated to 80 to 85° C. VA-086(9.82 g), an initiator was added in lotwise manner. First lot of VA-086was added in about 4 hrs at 80 to 85° C. The reaction mixture wasmaintained at 80 to 85° C. for a further 8 hrs. Second lot of VA-086 wasadded in about 2 hrs at 80 to 85° C. and the reaction mixture wasmaintained for a further 10 hrs at 80 to 85° C. The mass was cooled to40 to 50° C. and the solution was slowly charged to Methanol (1843 ml)(quenching). Two successive washings of methanol (921 ml) were given tothe wet cake of polyallylamine hydrochloride by stiffing at 25 to 35° C.for 45 min. The resultant mass was dried at 65 to 70° C. under vacuum.

Example 2 Preparation of Sevelamer Hydrochloride

50 g Poly(allylamine hydrochloride) and 75 ml water were mixed at 25 to35° C. to get a clear solution. The solution was further cooled to 5 to15° C. and 13.68 g sodium hydroxide solution in water was added to thereaction mass at 5 to 15° C. and stirred for 30 minutes, 400 ml tolueneand 2 g SPAN-85 were added to it at 5 to 15° C. The temperature of thereaction mixture was then raised to 20 to 25° C. and maintained for 15min. The reaction mixture was filtered to remove any extraneous matterat 25 to 35° C. The temperature of the filtrate was further raised to 55to 60° C. and maintained for 15 minutes. 4.5 g epichlorohydrin was addedat constant temperature of 55 to 60° C. to reaction mixture andmaintained for 3 hr at 55 to 60° C. The reaction mixture was cooled to25 to 35° C. and product was isolated by centrifugation. The wet cakewas further sludged with water (3×750 ml) for 45 min at 25 to 50° C. andfiltered and dried in FBD at 25 to 90° C.

Chloride content 4.45 meq/g Phosphate binding capacity by IC method 5.97mmol/g. Degree of crosslinking 16.4% Yield 77.0% w/w

Example 3

Poly(allylamine hydrochloride) (50 g) and water (75 ml) were mixed at 25to 35° C. to get a clear solution. The solution was further cooled to 5to 15° C. and 14.41 g sodium hydroxide solution in water was added tothe reaction mass at 5 to 15° C. and stirred for 30 min. Toluene (400ml) and SPAN-85 (2 g) were added to it at 5 to 15° C. The temperaturewas then raised to 20 to 25 C and maintained for 15 min. The reactionmixture was filtered to remove any extraneous matter at 25 to 35° C. Thetemperature of the filtrate was further raised to 55 to 60° C. andmaintained for 15 min. Epichlorohydrin (3.395 g) was added to thereaction mixture at constant temperature of 55 to 60° C. and maintainedfor 3 hr at 55 to 60° C. The reaction mixture was cooled to 25 to 35° C.and product was isolated by centrifugation. The wet cake was furthersludged thrice with water (3×750 ml) for 45 min. at 25 to 50° C. andfinally with isopropanol (750 ml) followed by filteration and dried intray driers at 25 to 90° C.

Chloride content  4.8 meq/g. Phosphate binding capacity by IC method5.39 mmol/g. Degree of crosslinking 13.8% Yield 70.4% w/w

Example 4

Poly(allylamine hydrochloride) (50 g) and water (75 ml) were mixed at 25to 35. ° C. to get a clear solution. The solution was further cooled to5 to 15° C. and 14.41 g sodium hydroxide solution in water was added tothe reaction mass at 5 to 15° C. and stirred for 30 min. Toluene (400ml) and SPAN-85 (2 g) were added to it at 5 to 15° C. The temperature ofthe reaction mixture was then raised to 20 to 25° C. and maintained for15 min. The reaction mixture was filtered to remove any extraneousmatter at 25 to 35° C. The temperature was further raised to 55 to 60°C. and maintained for 15 min. Epichlorohydrin (4.5 g) was added to thereaction mixture at constant temperature (55 to 60° C.) to reactionmixture and maintained for 3 hr at 55 to 60° C. The reaction mixture wascooled to 25 to 35° C. and product was isolated by centrifugation. Thewet cake was further sludged thrice with water (3×750 ml) for 45 min. at25 to 50° C. and dried in FBD at 25 to 90° C.

Chloride content 4.68 meq/g. Phosphate binding capacity by IC method5.51 mmol/g. Degree of crosslinking 15.38% Yield 76.0% w/w

Example 5

Poly(allylamine hydrochloride) (50 g) and water (75 ml) were mixed at 25to 35° C. to get a clear solution. The solution was further cooled to 5to 15° C. and 14.41 g sodium hydroxide solution in water was added tothe reaction mass at 5 to 15° C. and stirred for 30 min. Toluene (400ml) and SPAN-85 (2 g) were added to it at 5 to 15° C. The temperaturewas then raised to 20 to 25° C. and maintained for 15 min. The reactionmixture was filtered to remove any extraneous matter at 25 to 35° C. Thetemperature of the filtrate was further raised to 55 to 60° C. andmaintained for 15 min. epichlorohydrin (4.5 g) was added to the reactionmixture at constant temperature of 55 to 60° C. to reaction mixture andmaintained for 3 hr at 55 to 60° C. The reaction mixture was cooled to25 to 35° C. and product was isolated by centrifugation. The wet cakewas further sludged with water (3×750 ml) for 45 min. at 25 to 50° C.and finally with isopropanol (750 ml) followed by filtration. The wetcake is then dried in tray driers at 25 to 90° C.

Chloride content  5.02 meq/g. Phosphate binding capacity by IC method 5.26 mmol/g. Degree of crosslinking 15.17% Yield  75.0% w/w

Example 6

Co-sifted Sevelamer hydrochloride (1.2 kg) and microcrystalline (AvicelPH 101) (0.28 kg) and mixed in a rapid mixer granulator (RMG). Prepareda solution of polyethylene glycol 6000 (0.135 kg) in purified water andadded to the mixture in the RMG. Prepared a solution of povidone K 30(0.153 kg) in isopropyl alcohol and added to the RMG. Dried thegranulated mass. Milled the dried mass using multimill/sifter andfurther using ball mill to obtain granules which pass through 60# sieve.Lubricated the granules in a conta blender using colloidal silicondioxide (0.009 kg) and stearic acid (0.009 kg). Compressed thelubricated granules on a conventional tabletting machine to produce 400mg tablets of Sevelamer hydrochloride. Sevelamer hydrochloride tablets800 mg was prepared using blend double the weight of that used in 400 mgtablets. Core tablets were further film coated by aqueous process till aweight gain in the range of about 4.0% to about 6.0% is achieved.

Example 7

Mixed mannitol (0.164 kg) and pre-sifted Sevelamer hydrochloride (1.2kg) in a rapid mixer granulator. Purified water was added to wet themixture. Prepared the binder solution by dissolving the ethyl cellulose(0.128 kg) in isopropyl alcohol. Binder solution was added to themixture in RMG which was under fast speed mixing using a peristalticpump to obtain a cohesive mass. Milled the dried mass usingmultimill/sifter and further using ball mill to obtain granules whichwere passed through 60# sieve. Lubricated the granules in a contablender using colloidal silicon dioxide (0.009 kg) and stearic acid(0.009 kg). Compressed the lubricated granules on a conventionaltabletting machine to produce 400 mg tablets of Sevelamer hydrochloride.Sevelamer hydrochloride tablets 800 mg was prepared using blend doublethe weight of that used in 400 mg tablets. Core tablets were furtherfilm coated by aqueous process till a weight gain in the range of about4.0% to about 6.0% was achieved.

Example 8

Sevelamer hydrochloride 1.2 kg was co-sifted along with Pearlitol SD 200(about 0.160 kg) through 20 mesh S S Sieve on vibrosifter, and loadedinto the rapid mixer granulator and mixed for about 5 minutes. Bindersolution prepared by dissolving about 127.5 gm Ethocel N 7 Pharm in 400gm Isopropyl alcohol was added to the dry mix in the Rapid mixergranulator under fast speed. Addition was done slowly in a continuousstream. After addition of binder further mixing was done at high speedto obtain a cohesive granulated mass. Granulated mass was then air driedwithout temperature in the Glatt drier or Restch drier and further driedat about 40 to 45 deg C. till loss on drying value not more than 5.0%w/w was achieved. Dried mass was milled, lubricated and compressedaccording to the procedure described in Example 6. In an alternatemethod a Planetary mixer was used for the granulation.

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, itwill be understood that the practice of the invention encompasses all ofthe usual variations, adaptations and/or modifications as come withinthe scope of the following claims and their equivalents.

1. A process for wet granulating sevelamer, the process comprising thesteps of: a) obtaining sevelamer; b) mixing said sevelamer with agranulation liquid, i) said granulation liquid comprised of at least onenon-aqueous solvent, ii) said granulation liquid is further comprised offrom 0% to less than about 20% water; and c) granulating the sevelamerby wet granulation to produce granulated sevelamer.
 2. The process ofclaim 1, wherein the non-aqueous solvent comprises short-chain alcohol.3. The process of claim 2, wherein the non-aqueous solvent comprisesethyl alcohol.
 4. The process of claim 2, wherein the non-aqueoussolvent comprises isopropyl alcohol.
 5. The process of claim 4, whereinsaid granulation liquid is further comprised of about 5% water.
 6. Theprocess of claim 1, wherein the granulation liquid further comprisesbinder.
 7. The process of claim 6, wherein said binder comprisespolyvinylpyrrolidone.
 8. The process of claim 1, wherein before thesevelamer is mixed with the granulation liquid, the sevelamer is pre-wetwith a wetting solution.
 9. The process of claim 8, wherein the wettingsolution comprises water.
 10. The process of claim 9, wherein thewetting solution further comprises polyethylene glycol.
 11. The processof claim 1, wherein the granulated sevelamer has a hydration of not morethan about 7% as measured by Karl Fischer analysis.
 12. The process ofclaim 1, wherein the granulated sevelamer exhibits a weight loss ondrying of not more than about 15%.
 13. The process of claim 2, whereinthe granulating is selected from the group consisting of: wet high-sheargranulation and wet spray granulation.
 14. A composition of mattercomprising sevelamer prepared by the process of claim
 1. 15. Thecomposition of matter of claim 14, further comprising at least onepharmaceutically-acceptable excipient, said composition in oral tabletform, said tablet providing up to about 1 gram of sevelamer per tablet,said tablet substantially disintegrating in HCl solution within not morethan about 3 minutes.
 16. In a process of granulating sevelamer, theimprovement comprising wet granulation using a granulation liquidcomprised of at least one non-aqueous solvent and from 0% to less thanabout 20% water, whereby the sevelamer may be wet granulated using thegranulation liquid.
 17. Sevelamer, wet granulated with a granulationliquid comprised of at least one non-aqueous solvent and from 0% to lessthan about 20% water.